Psoriasis is a chronic skin disease, with a high percentage of genetic pre-disposition. The disease fluctuates between acute exacerbation and times of complete standstill. Patients suffering from psoriasis may be severely handicapped because of the external characteristics of the disease. This affects all parts of life, such as the professional career as well as the personal and private life.
The therapeutic possibilities available until the therapy according to the invention are limited, in particular for patients with moderate to severe psoriasis, and many of them provide only a temporary and short-term improvement, and/or have severe adverse effects/side effects. Since psoriasis has a high recurrence rate, the majority of patients have to undergo long-term treatment.
Fumaric acid esters have been used for the treatment of moderate to severe psoriasis for more than 30 years. In 1994 a defined mixture of dimethyl fumarate and monoethyl fumarate salts was approved in Germany—Fumaderm® initial/Fumaderm®. One enteric coated tablet of Fumaderm® contains the following active ingredients: dimethylfumarate 120 mg; ethylhydrogenfumarate, calcium salt 87 mg; ethylhydrogenfumarate, magnesium salt 5 mg; ethylhydrogenfumarate, zink salt 3 mg, and the following other ingredients: croscarmellose-sodium, talc, magnesium stearate, coloring agents E 171 and E 132, methacrylic acid-methylmethacrylate-copolymer (1:1), methacrylic acid-ethylacrylate-copolymer (1:1), Macrogol 6000, simethicone, povidone, triethyl citrate, microcrystalline cellulose, highly disperse silicon dioxide [Summary of Product Characteristics, Fumaderm®, version January 2009]. By today Fumaderm® represents about 66% of all prescriptions for systemic therapy of psoriasis in Germany. However, a high frequency of side effects causes some patient discontinuation early in treatment. It is contemplated that the gastrointestinal side effects and flushing can, at least partially, be explained by the release properties of the prescription formulation, leading to high local concentrations in the intestines.
The present inventors contemplate that an improved treatment regimen may be obtained by administration of a pharmaceutical composition that is designed to deliver the active substance in a controlled manner, i.e. in a manner that is prolonged, sustained, retarded, slow and/or delayed compared with the commercially available product.
Fumaric acid esters, such as dimethyl fumarate, can be subject to degradation and hydrolysis. It is e.g. known that dimethyl fumarate is more prone to hydrolysis in an alkaline/less acidic environment, c.f. more acidic environments (Litjens et al, “In vitro pharmacokinetics of anti-psoriatic fumaric acid esters”, BMC Pharmacology 2004, 4:22). Thus, dimethyl fumarate is considered to be more prone to hydrolysis in the small intestine, c.f. the gastric ventricle. In addition to the pH effect described above, esterases are considered to contribute to hydrolysis of fumaric acid esters.
WO 2006/037342 discloses controlled release pharmaceutical compositions comprising fumaric acid ester(s) as active substance(s) wherein the controlled release profile results in a reduction in GI (gastro-intestinal) related side-effects.